tbuckley/cabot-search huggingface dataset:
Abstract 3770: Hypoxia-induced circular RNA<i>circSFMBT2</i> inhibits tumor malignancy in breast cancer cells
Authors: Chia-Ming Liu, Yi-Chun Ke, Liang-Chuan Lai
Journal: Cancer Research (2023)

Abstract Breast cancer is the most prevalent cancer among women, and the second major cause of cancer-related deaths in women worldwide. The hypoxic microenvironment of solid tumors is formed in the progress of carcinogenesis, which leads to more malignant and treatment resistance. Recently, circular RNAs (circRNA), a kind of noncoding RNA, were discovered to influence the progress of tumorigenesis, and were induced under hypoxia. However, the regulation and functions of hypoxia-induced circRNA in breast cancer remain unclear. Therefore, the purpose of this study is to identify the regulatory mechanism and its function of a hypoxia-induced circRNAs, circSFMBT2, in breast cancer cells. Firstly, hypoxia-responsive circRNA candidates in breast cancer MCF-7 cells under different oxygen concentrations were identified by RNA-sequencing. Among the differentially expressed circRNAs, circSFMBT2 was chosen for further experiments. The up-regulation of circSFMBT2 under hypoxia was validated by quantitative RT-PCR. The functional assays showed that overexpression of circSFMBT2 inhibited cell proliferation, migration, invasion, and epithelial-mesenchymal transition. Next, in order to investigate the regulatory mechanisms of circSFMBT2, nuclear and cytoplasm fractionation was performed. The results showed circSFMBT2 predominantly localized in the cytoplasm, indicating that the regulatory mechanism of circSFMBT2 might be via interaction with microRNA or RNA-binding proteins (RBP). In order to identify the RBPs, bioinformatic tools, RBPDB, ATtRACT, and RBPmap, were first used to predict the candidate RBPs and validated by RNA pulldown assays. The RNA-binding protein PABPC1 was proved to bind with circSFMBT2. On the other hand, the potential sponging microRNAs were predicted by ENCORI and miRDB, followed by qRT-PCR. No miRNAs were shown to bind with circSFMBT2. Lastly, the functions of circSFMBT2 were explored by identifying its downstream genes using Affymetrix microarrays. The top 10 differentially expressed genes were chosen for validation by quantitative RT-PCR. However, no genes showed significant changes in cells overexpressing circSFMBT2, implying the regulation of circSFMBT2 might not be at the transcriptional level. In summary, circSFMBT2 was able to inhibit the cellular function of breast cancer and bind to PABPC1. With a deeper understanding of the regulatory mechanisms of circSFMBT2, we hope to develop a novel treatment regime for breast cancer. Citation Format: Chia-Ming Liu, Yi-Chun Ke, Liang-Chuan Lai. Hypoxia-induced circular RNAcircSFMBT2 inhibits tumor malignancy in breast cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3770.
Abstract 2395: A bioluminescent probe for detection and imaging of heparanase enzymatic activity
Authors: Johnathan Somers, Kelton Schleyer, Jun Liu, Zhishen Wang, Arjun Kafle, Lina Cui
Journal: Cancer Research (2023)

Abstract Cancers of all types have been shown to overexpress the carbohydrate-processing enzyme heparanase during angiogenesis and invasion, and this enzymatic activity correlates positively with tumor stage and the presence of metastases. While detection of heparanase enzymatic activity holds potential for cancer diagnosis and staging, no probe has been achieved for in vivo systems. We have recently developed fluorogenic heparanase probes for single-step detection of in vitro heparanase enzymatic activity, drastically simplifying the detection of heparanase activity. The modular chemistry allows us to extend the utility further to improve the sensitivity of in vitro heparanase activity detection and enable in vivo detection. Thus, we have developed a bioluminescent heparanase probe, which upon activation by heparanase produces a substrate of firefly luciferase, a standard reporter enzyme for in vivo monitoring of tumor progression. This probe will be validated in multi-well assays of heparanase activity, and applied in real-time correlation of heparanase activity and tumor progression in, fLuc+ tumors in animal models. These studies hold promise in enabling highly sensitive detection of heparanase activity both in vitro and in vivo, and in allowing future research of real-time monitoring of heparanase activity with the tumor progression. Citation Format: Johnathan Somers, Kelton Schleyer, Jun Liu, Zhishen Wang, Arjun Kafle, Lina Cui. A bioluminescent probe for detection and imaging of heparanase enzymatic activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2395.
Abstract 2066: Visualization and analysis of cancer genomics data using UCSC Xena
Authors: Mary Goldman, Brian Craft, Jingchun Zhu, David Haussler
Journal: Cancer Research (2023)

Abstract UCSC Xena (http://xena.ucsc.edu/) is a web-based visual integration and exploration tool for multi-omic data and associated clinical and phenotypic annotations. Researchers can easily view and explore public data, their own private data, or both using the Xena Browser. Private data are kept on the researcher's computer and are never uploaded to our public servers. We support Mac, Windows, and Linux. Questions Xena can help you answer: * Is overexpression of this gene associated with lower/higher survival? * What genes are differentially expressed between these two groups of samples? * What is the relationship between mutation, copy number, expression, etc for this gene? Xena showcases seminal cancer genomics datasets from TCGA, the Pan-Cancer Atlas, GDC, PCAWG, ICGC, and more; a total of more than 1500 datasets across 50 cancer types. We support virtually any type of functional genomics data: SNPs, INDELs, copy number variation, gene expression, ATAC-seq, DNA methylation, exon-, transcript-, miRNA-, lncRNA-expression and structural variants. We also support clinical data such as phenotype information, subtype classifications and biomarkers. All of our data is available for download via python or R APIs, or using our URL links. Our signature Visual Spreadsheet view shows multiple data types side-by-side enabling discovery of correlations across and within genes and genomic regions. We also have dynamic Kaplan-Meier survival analysis, powerful filtering and subgrouping, differential gene expression analysis, charts, statistical analyses, genomic signatures, and the ability to generate URLs to live views. We link out to the UCSC Genome Browser as well as MuPIT/CRAVAT and TumorMap. New features include: * Genome-wide differential gene expression analysis * Select samples directly from the screen for filtering and creating subgroups * Violin plots on any numerical data * Loading of Microsoft Excel files Our beta prototype site for visualizing single-cell data delivers million-cell-scale multi-omics data for interactive visualization in a web browser. Contact us for access to our beta prototype site. If you use us please cite our publication in Nature Biotechnology: https://www.nature.com/articles/s41587-020-0546-8 Citation Format: Mary Goldman, Brian Craft, Jingchun Zhu, David Haussler. Visualization and analysis of cancer genomics data using UCSC Xena [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2066.
Abstract 2357: Fibroblast activation protein (FAP) expression as a target for colorectal cancer treatment
Authors: Anna L. Lippert, Katherine A. Johnson, Cheri A. Pasch, Wei Zhang, Kristina A. Matkowskyj, Aaron M. LeBeau, Dustin A. Deming
Journal: Cancer Research (2023)

Abstract Background: Fibroblast Activation Protein (FAP) is a protein expressed by cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) of epithelial cancers. There is potential interest in the use of FAP as a way to selectively target cancers, including colorectal cancer (CRC). Here we examine the expression of FAP in human colorectal cancers across stages and compare that expression to expression in normal colon and liver tissue. Additionally, we examine the correlation of FAP expression with key CRC clinical and biologic features to aid in potentially determining which CRC patients would be the most likely to benefit from FAP-directed therapies. Methods: CRC and adjacent normal tissue samples spanning all stages of disease were collected across 243 patients. Immunohistochemistry (IHC) was used to evaluate FAP, MMP2, αSMA, and PDPN expression and quantified on an intensity scale from 0-3+. These scores were split into low (average score &amp;lt;2) and high (average score &amp;gt;/=2) groups. IHC was used to determine mismatch repair status by staining for MLH1, MSH2, MSH6, and PMS2. Separate samples from these patients were sequenced with the Qiagen Comprehensive Cancer Panel and analyzed for APC, KRAS, BRAF, PIK3CA, and TP53 mutations. Results: Of 149 normal colon tissue sections, 99% had low FAP expression and 94% of those had no FAP expression. Of the 87 normal liver tissue sections, 99% had low FAP expression. In CRC sections, 58% had high FAP expression. Those patients &amp;gt;50 years of age had cancers with a higher rate of FAP expression (p=0.02). There was no correlation with FAP expression and sex, stage of disease, or sidedness. In cancers with BRAF V600 mutations, 91% have high FAP expression (x2 = 0.02). There is a trend for higher FAP expression in cancers possessing APC, KRAS, PIK3CA, or TP53 mutations (x2=NS). In correlating FAP with other CAF markers, MMP2 had the greatest correlation (Spearman’s Rho = 0.56). FAP is moderately associated with αSMA and PDPN (Spearman’s Rho = 0.33, 0.38). Conclusion: FAP is an exciting therapeutic target for CRC due to its cancer selectivity. Here, we demonstrate that FAP marks a rather independent subset of CRCs, though there is particular interest in the BRAF V600 mutant cancers given the high expression and poor prognosis of this subtype. Further investigation is needed to further develop FAP-directed therapies. Citation Format: Anna L. Lippert, Katherine A. Johnson, Cheri A. Pasch, Wei Zhang, Kristina A. Matkowskyj, Aaron M. LeBeau, Dustin A. Deming. Fibroblast activation protein (FAP) expression as a target for colorectal cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2357.
Abstract 1788: A novel costimulatory signaling domain for chimeric antigen receptor-engineering
Authors: Hyun-Il Cho, Chung-Hyo Kang, Sang-Eun Lee, Mi-So Kim, Bo-Ra Lim, Jung-Min Ha, Hyun-Jung Sohn, Tai-Gyu Kim
Journal: Cancer Research (2023)

Abstract Chimeric antigen receptor (CAR)-engineered adoptive cell therapy has demonstrated a feasible, attractive “off-the-shelf” approach against various malignancies. Success of CAR-engineered cell therapy depends primarily on providing optimized costimulatory signals capable of achieving robust cell proliferation, persistence, and antitumor reactivity. We describe here the capability of a novel CD30-derived costimulatory signaling domain to generate effective CAR-redirected cells capable of eradicating hematological and solid cancers. After establishing CD19-redirecting second-generation CARs incorporating the CD30-derived intracellular signaling domain and third-generation CARs combining CD30 with either CD28 or 4-1BB, the effector functionality of CAR-transduced T cells was assessed in vitro and in vivo. Further, we evaluated the efficacy of epithelial cell adhesion molecule (EpCAM)-targeting third-generation CD30-encompassing CAR constructs for targeting solid tumors. The CD30-signaling CAR-T cells exhibited similar levels of cell proliferation, cytolytic efficacies, and cytokine secretion in vitro, and demonstrated improved tumor regression and prolonged survival in vivo with increased persistence of the CAR-T cells as those of other CARs with CD28 or 4-1BB costimulatory domain, which are currently in clinical use. Also, third-generation CARs including the CD30 costimulatory domain retained potent antitumor efficacies in vitro and in vivo independent of their position or type of partner costimulatory domain. More significantly, EpCAM-targeting CAR-T cells containing CD30-signaling domain revealed effective cytolytic activities correlating with EpCAM expression levels in the target cells. Our results demonstrate that the CD30-derived costimulatory domain could be an alternative for developing CAR-engineered therapeutics which may be applicable for various designs of CAR constructs, with an emphasis on effectiveness against solid tumors. Citation Format: Hyun-Il Cho, Chung-Hyo Kang, Sang-Eun Lee, Mi-So Kim, Bo-Ra Lim, Jung-Min Ha, Hyun-Jung Sohn, Tai-Gyu Kim. A novel costimulatory signaling domain for chimeric antigen receptor-engineering [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1788.
Abstract 6095: A DNA damaging agent affects <i>BRCA2</i> exon 3-skipping
Authors: Jordan R. Werner, Hiba Siddiqui, Ethan Castillo, Mohammed Ansari, James D. Fackenthal
Journal: Cancer Research (2023)

Abstract Introduction: BRCA2 is a tumor suppressor that participates in DNA repair. Inherited pathogenic mutations in BRCA2 are associated with a 38%-84% risk for breast cancer and a 16.5%-27% risk for ovarian cancer. BRCA2 exon 3, which encodes a binding site for the interacting proteins EMSY and PALB2, is frequently skipped during alternative splicing events, often due to spliceogenic mutations, but also for as yet uncharacterized environmental conditions. A genomic deletion that results in complete allelic loss of exon 3 has been shown to be pathogenic, yet sequence variants that result in increased frequency of exon 3-skipping have been shown to be non-pathogenic. Thus, the allele-specific ability of BRCA2 to contribute to DNA repair is affected by the level of exon 3-skipping. In this study we explore the effects of the topoisomerase inhibitor doxorubicin on the frequency of BRCA2 exon 3-skipping. Isoform-specific end-point RT-PCR shows that doxorubicin increases the frequency of BRCA2 exon 3-skipping in the breast cancer cell line MCF7 at concentrations below those required for promoting apoptosis. Methods: MCF7 cells were treated with doxorubicin according to standard protocols. IC50 levels of doxorubicin were determined using a crystal violet assay. Flow cytometry was performed using standard protocols. RNA was prepared using Qiagen reagents and amplified with Invitrogen One-Step RT-PCR reagents. Isoform-specific RT-PCR primers were designed to amplify the full-length region surrounding BRCA2 exon 3 independently from the region left by an exon-skipping event (∆3). RT-PCR products were visualized using agarose gel electrophoresis. Results and Conclusion: Results suggest that doxorubicin increases the level of BRCA2 exon 3-skipping in MCF7 at concentrations below those required for promoting apoptosis. This suggests doxorubicin may compromise the DNA repair functions of BRCA2 and other alternatively spliced mRNAs, which may contribute to the therapeutic benefits and/or toxicity of the drug. Citation Format: Jordan R. Werner, Hiba Siddiqui, Ethan Castillo, Mohammed Ansari, James D. Fackenthal. A DNA damaging agent affects BRCA2 exon 3-skipping [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6095.
Abstract 4281: Data driven refinement of gene signatures for enrichment analysis and cell state characterization
Authors: Alexander T. Wenzel, Pablo Tamayo, Jill P. Mesirov
Journal: Cancer Research (2023)

Abstract The use of gene expression data has been crucial to the functional characterization of changes in molecular pathway activity and for identifying targets for novel treatments. However, the interpretation of this data is complicated by its high dimensionality and the difficulty of identifying biological signals within a list of differentially expressed genes. Gene Set Enrichment Analysis (GSEA) is a standard method for identifying pathway enrichment in gene expression data by testing whether a set of genes whose expression would indicate the activity of a specific process or phenotype are coordinately up- or downregulated more than would be expected by chance. As GSEA relies on high quality gene sets with coordinately regulated member genes, we maintain the Molecular Signatures Database (MSigDB) which contains 9 collections of curated gene sets representing different biological pathways and processes. Over time, we have observed that some of the MSigDB gene sets, especially those that are manually curated or defined in a very specific biological context, may not provide a sensitive and specific enough co-regulation signature. In response, we have created a data-driven, matrix-factorization-based refinement method to build more sensitive and specific gene sets. This method incorporates large-scale datasets from multiple sources such as the Cancer Dependency Map as well as curated protein-protein interaction networks. We will present the initial results of this refinement method and our ongoing work which will yield a new collection of refined gene sets that will be made freely available in MSigDB for use with GSEA and many other applications. Citation Format: Alexander T. Wenzel, Pablo Tamayo, Jill P. Mesirov. Data driven refinement of gene signatures for enrichment analysis and cell state characterization. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4281.
Long-term Outcomes Following a Comprehensive Quality Assurance and Process Improvement Endeavor to Minimize Opioid Use After Kidney Transplant
Authors: Taylor Carcella, Neha Patel, Jarrod Marable, Shipra Bethi, James Fleming, Prabhakar Baliga, Derek DuBay, David Taber, Vinayak Rohan
Journal: JAMA Surgery (2023)

Opioid use following kidney transplant is associated with an increased risk of graft loss and mortality. Opioid minimization strategies and protocols have shown reductions in short-term opioid use after kidney transplant.
Proteostasis Modulation in Germline Missense von Hippel Lindau Disease
Authors: Prashant Chittiboina, Debjani Mandal, Alejandro Bugarini, David T. Asuzu, Dustin Mullaney, Panagiotis Mastorakos, Stefan Stoica, Reinier Alvarez, Gretchen Scott, Dragan Maric, Abdel Elkahloun, Zhengping Zhuang, Emily Y. Chew, Chunzhang Yang, Marston Linehan, Russell R. Lonser
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Missense mutated von Hippel Lindau (VHL) protein (pVHL) maintains intrinsic function but undergoes proteasomal degradation and tumor initiation and/or progression in VHL disease. Vorinostat can rescue missense mutated pVHL and arrest tumor growth in preclinical models. We asked whether short-term oral vorinostat could rescue pVHL in central nervous system hemangioblastomas in patients with germline missense VHL. Patients and Methods: We administered oral vorinostat to 7 subjects (ages 46.0 ± 14.5 years) and then removed symptomatic hemangioblastomas surgically (ClinicalTrials.gov identifier NCT02108002). Results: Vorinostat was tolerated without serious adverse events by all patients. pVHL expression was elevated in neoplastic stromal cells compared with untreated hemangioblastomas from same patients. We found transcriptional suppression of downstream hypoxia-inducible factor (HIF) effectors. Mechanistically, vorinostat prevented Hsp90 recruitment to mutated pVHL in vitro. The effects of vorinostat on the Hsp90–pVHL interaction, pVHL rescue, and transcriptional repression of downstream HIF effectors was independent of the location of the missense mutation on the VHL locus. We confirmed a neoplastic stromal cell–specific effect in suppression of protumorigenic pathways with single-nucleus transcriptomic profiling. Conclusions: We found that oral vorinostat treatment in patients with germline missense VHL mutations has a potent biologic effect that warrants further clinical study. These results provide biologic evidence to support the use of proteostasis modulation for the treatment of syndromic solid tumors involving protein misfolding. Proteostasis modulation with vorinostat rescues missense mutated VHL protein. Further clinical trials are needed to demonstrate tumor growth arrest.
Fictional emotions and emotional reactions to social robots as depictions of social agents
Authors: Jonas Blatter, Eva Weber-Guskar
Journal: Behavioral and Brain Sciences (2023)

Following the depiction theory by Clark and Fischer we would expect people interacting with robots to experience fictional emotions akin to those toward films or novels. However, some people's emotional reactions toward robots display the motivational force typical to non-fictional emotions. We discuss this incongruity and offer two suggestions on how to explain it while maintaining the depiction theory.